Carbamic acid derivatives as selective immunosuppresive agents

ABSTRACT

Novel cyclized ω-carboxyethyl mono or dithiocarbanilic acids are disclosed as immunoregulatory agents, useful in the treatment of organ transplant reject phenomenon and autoimmune diseases particularly where a delayed hypersensitivity component has been established, such as multiple sclerosis. 
     Additionally described is the use of certain cyclized ω-carboxyalkyl mono- or dithiocarbamic acids and certain cyclized ω-carboxyalkyl mono- or dithiocarbamic acids.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention provides certain novel organic compounds whichhave immunoregulatory properties, rendering these compounds useful inthe treatment of hyperimmunity diseases. Moreover, the present inventionprovides for the immunoregulatory use of certain organic compounds inhyperimmunity diseases.

Among the novel compounds herein and the compounds employed in the novelmethods herein as pharmacological agents are cyclized substitutedω-carboxymethyl and ω-carboxyethyl mono- or dithiocarbanilic acids andcyclized substituted ω-carboxymethyl and ω-carboxyethyl mono- ordithiocarbamic acids.

Cyclized ω-carboxymethyl and ω-carboxyethyl mono- or dithiocarbanilicacids have the structural formula: ##STR1## wherein Y is selected fromthe group consisting of oxygen and sulfur; wherein a is the integer oneor two; and corresponding cyclized ω-carboxymethyl and ω-carboxyethylmono- or dithiocarbamic acids are compounds of the structural formula:##STR2## wherein Y and a are as defined above.

Compounds of the above structures are known as thiazines and thiazolineswhich may be rhodanines.

2. The Prior Art

Certain thiazines and rhodanines are known in the art as useful for awide variety of purposes. Compounds within these classes arestructurally derived from corresponding intermediates which areprepared, for example, by reactions between ω-mercaptoalkylcarboxy acidsand isocyanates or isothiocyanates. Subsequent dehydration results ininternal cyclization of the intermediates with yields of thiazines andrhodanines. Dehydration is accomplished with addition of aceticanhydride containing a few drops of strong acid. Methods to preparecertain intermediates and the cyclized derivatives of the presentinvention are well known.

See, for example, Garroway, J. L., J. Chem. Soc. 1961:3733-5 whichdescribes ω-carboxyalkyl dithiocarbanilic acids as precursors forcorresponding cyclic lactams, i.e. rhodanines and thiazine analogs. Forproduction of rhodanine or thiazine analogs from correspondingω-carboxyalkyl dithiocarbanilic acid precursors see also U.S. Pat. Nos.3,781,434; 3,732,216 and 3,816,627; Brown, F. C., et al., J.A.C.S.78:384 (1956); Werbel, L. M., et al., J. Med. Chem. 11 (2):364 (1968)and a Belgian application No. 862-725, filed July 13, 1978 havingDerwent No. 33497A/19 by Yoshitomo Pharm. Ind. KK (also now issued asU.S. Pat. No. 4,169,899).

The U.S. Patents noted above describe the antiarthritic use of twogroups of substituted thiazines, including, inter alia, compounds of theformula: ##STR3## wherein according to U.S. Pat. Nos. 3,781,434 and3,732,216 "A" represents phenyl substituted by a halogen such aschlorine, bromine and fluorine or trifluoromethyl and wherein accordingto U.S. Pat. No. 3,816,627 "A" represents a heterocyclic moiety,particularly one containing nitrogen. In the Yoshitomo BelgianApplication "A" includes an alkylene linkage having one to five carbonsbetween the nitrogen on the thiazine and any other moiety thereon whichtherefore distinguishes it from the present invention.

The remaining references listed above describe certain rhodanines asanti-fungicidal, anti-bacterial and anti-malarial agents.

W. Hanefeld, Archio Der Pharmazie Vol. 308, (1975) pp. 450-454 describesfungiostatic properties of certain dioxo and thioxotetrahydro-1,3-thiazines.

Immunoregulatory agents may be either immunosuppressive orimmunostimulatory. For the purposes of this invention, the process ofimmunosuppression is the desired response to a disease or othercondition which results from hyperimmunity in the animal or patient.Immunosuppressive use of ω-carboxyalkyl and ω-(alkoxycarbonyl)alkylesters of dithiocarbanilic acid and certain aryl-substituted acidsrelated thereto are found in U.S. Pat. No. 4,110,444 and copending Ser.No. 848,433, now abandoned. For a comprehensive review of the use ofimmunosuppressive agents in the treatment of hyperimmunity diseases, seeCamiener, G. W., et al., Progress in Drug Research 16:67 (1972) andWechter, W. J., et al., Progress in Drug Research 20:573 (1976).

Many known immunosuppressive agents are cytotoxic and are believed inpart, if not exclusively, to accomplish the immunosuppressive effectsvia a cytotoxic mechanism on the immunoactive organs (e.g. bone marrowand thymus) and on the proliferating dynamic primary and secondarylymphoid tissue. For example, known antineoplastic agents such ascyclophosphamide, have been used in the treatment of arthritis. SeeSkinner, M. D., et al., Rheumatology 5:1 (1974).

Finally, anthelmintics such as niridazole have been employedimmunosuppressively to control allograft rejection; while anotheranthelmintic, levamisole, is apparently a non-specific stimulator of theimmune system. See Daniels, J. D., et al., J. Immuno 115:1414 (1975) andRenorex, G., et al., J. Immun. 109:761 (1972).

SUMMARY OF THE INVENTION

The present invention provides novel organic compounds selected from thegroup consisting of: ##STR4## wherein R' is alkyl carbonyl with alkyl offrom one to four carbon atoms, inclusive; or ##STR5##

R" is selected from the group consisting of chloro, bromo, fluoro andtrifluoromethyl; and

R₂ is selected from the group consisting of hydrogen and acylamino withacyl of from one to four carbon atoms, inclusive;

n₁ is an integer of from one to three;

n₂ is an integer of from one to five;

n₃ is an integer of from three to five;

Y is selected from the group consisting of oxygen and sulfur.

The invention also relates to a method of producing immunosuppression ina mammal exhibiting a hyperimmunity disease which comprises:

systemically administering in a pharmaceutically acceptable dosage acompound selected from the group consisting of: ##STR6##

T is selected from the group consisting of hydrogen, lower alkyl of fromone to four carbon atoms, inclusive, amino, carboxybenzylideneamino,chlorobenzylideneamino, anilino, phenylalkyl with alkyl of from one tofour carbon atoms, inclusive, cycloalkyl, and ##STR7##

wherein R is selected from the group consisting of hydrogen, alkyl offrom one to four carbon atoms, inclusive, alkoxy of from one to fourcarbon atoms, inclusive, thioalkoxy of from one to four carbon atoms,inclusive, alkylcarbonyl with alkyl of from one to four carbon atoms,inclusive, acyloxy with acyl of from one to four carbon atoms,inclusive, nitro, acylamino; and ##STR8##

R₃ and R₄ are the same or different and are selected from the groupconsisting of hydrogen, alkyl of from one to four carbon atoms,inclusive, --CH₂ CO₂ H and pharmaceutically acceptable salts thereof,alkoxymethyl with alkoxy of from one to four carbon atoms, inclusive,and indanylmethylene; such that when R₃ and R₄ are different one of theselection is hydrogen;

Y is selected from the group consisting of oxygen and sulfur;

n₁ is an integer of from one to three; and

a is the integer one or two; ##STR9## wherein

R₆ is selected from the group consisting of hydrogen and acylamino offrom one to four carbon atoms, inclusive;

R" is selected from the group consisting of chloro, bromo, fluoro andtrifluoromethyl;

Y is defined as above;

wherein n₂ is an integer of from one to five; ##STR10## wherein

R₇ and R₈ are the same or different and are selected from the groupconsisting of hydrogen, alkyl of from one to four carbon atoms,inclusive, carboxyalkyl and pharmaceutically acceptable salts thereof;such that when R₇ and R₈ are different one of the selection is hydrogen;

R" is selected from the group consisting essentially of bromo, chloro,fluoro and trifluoromethyl;

Y is defined as above; and

n₂ is an integer of from one to five; and ##STR11##

R" is selected from the group consisting of fluoro, chloro, bromo andtrifluoromethyl;

n₃ is an integer of from three to five, and

Y is as defined above;

wherein compounds (a'), (b'), (c') and (d') are all administered in anamount effective to ameliorate or cure said hyperimmunity disease.

The invention further relates to a method of immunosuppression in amammal exhibiting a hyperimmunity disease of the class comprisingtransplant rejection phenomena and autoimmune diseases such as psoriaticarthritis, systemic lupus erythemotosus, regional enteritis, chronicactive hepatitis, nephrotic syndrome, glomerulonephritis, lupusnephritis, ulcerative colitis and particularly where a delayedhypersensitivity component has been established such as multiplesclerosis, which comprises systemically administering in apharmaceutically acceptable dosage a compound of the formula: ##STR12##wherein W is pyridyl or ##STR13## wherein R" is selected from the groupconsisting of chlorine, bromine, fluorine, and trifluoromethyl;

wherein

n₂ is an integer of from one to five; and

Y is as defined above;

in an amount effective to ameliorate or cure said hyperimmunity disease.

A preferred embodiment of the invention is a method of producingselective immunosuppression in a mammal exhibiting a hyperimmunitydisease which comprises systemically administering in a pharmaceuticallyacceptable dosage a compound selected from the group consisting of:

3-(4-acetylaminophenyl)rhodanine;

5-(5-indanylmethylene)rhodanine;

3-(3-acetylphenyl)tetrahydro-2-thioxo-4H-1,3-thiazin-4-one;

3-(2-trimethylfluorophenyl)tetrahydro-2-thioxo-4H-1,3-thiazin-4-one;

3-(3-methylphenyl)tetrahydro-2-thioxo-4H-1,3-thiazin-4-one;

which are non-cytotoxic; and further also selected from the groupconsisting of:

3-phenylrhodanine;

3-(3-fluorophenyl)-5-acetylaminotetrahydro-2-thioxo-4H-1,3-thiazin-4-one;

3-(3-methoxyphenyl)tetrahydro-2-thioxo-4H-1,3-thiazin-4-one;

3-phenyl-5-carboxymethylene rhodanine;

3-(4-acetyloxyphenyl)tetrahydro-2-thioxo-4H-1,3-thiazin-4-one;

which exhibit a dosage dependent effect in addition to a lack ofcytotoxicity.

The novel cyclized ω-carboxyethyl dithiocarbamic acids of this inventionaccording to (a), (b) and (c) are characterized by substituents whichinclude alkylcarbonyl groups and acylamino moieties.

With respect to the alkylcarbonyl substitution referred to above, thereare included acetyl; ethylcarbonyl; n-propyl carbonyl; isopropylcarbonyl, n-butylcarbonyl; isobutyl carbonyl, and tertiary-butylcarbonyl moieties.

The acylamino moieties of the above named compounds include acetylamino,n-propionylamino, isopropionylamino, n-butyrylamino, isobutyrylamino,and tertiarybutyrylamino.

Novel compounds of the invention and compounds for methods of producingimmunosuppression of the invention are cyclized from ω-carboxyalkylmono- and di-thiocarbanilic acid intermediates by methods analogous tothose known in the art. For example, see the methods referred to in U.S.Pat. Nos. 3,732,216 and 3,781,434 described above. Both preparation ofintermediates and methods used to cyclize the intermediates to obtaincyclized compounds of the present invention are included in the abovementioned U.S. Patents as well as in U.S. Pat. No. 4,110,444 andapplication Ser. No. 848,433.

Accordingly, the intermediates from which the novel cyclized compoundsof the present invention are prepared are themselves prepared byreacting the appropriate arylisocyanate or arylisothiocyanate with theappropriate ω-carboxyalkylthiol. The reaction proceeds at ambienttemperature, being slightly exothermic, and is ordinarily completewithin about one hour. Preferred reaction solvents are benzene, xylene,toluene, aqueous trimethylamine or pyridine.

Recovery of the novel reaction products proceeds by conventional means,e.g., evaporation of solvent, or precipitation with acid. The requiredstarting materials for the transformations to obtain the intermediatesare commercially available or can be synthesized by methods well knownin the art.

Cyclization of the intermediates to novel compounds of the presentinvention is accomplished by heating the intermediates on a steam bathwith acetic anhydride containing a few drops of concentrated sulfuricacid. Alternative methods of preparation are not excluded herein.Frequently spontaneous cyclization to the 5-membered heterocycles occursduring isolation of the corresponding carboxylic acid.

With respect to the novel method described above for producingimmunosuppression in mammals exhibiting hyperimmunity disease, the useof this method in man is especially intended. However, the use in othermammals, such as canine, feline, bovine, and equine species is furtherintended.

With respect to the transplant rejection phenomenon the presentinvention relates to allograph rejection phenomena in organtransplantation, particularly vascularized grafts, and includinggraft-versus host disease in allographic bone marrow transplantation.

With regard to the autoimmune diseases encompassed by the presentmethod, there is included rheumatoid arthritis, psoriatic arthritis,systemic lupus erythematosus, regional enteritis, chronic activehepatitis, nephrotic syndrome, glomerulonephritis, lupus nephritis, andulcerative colitis. Further autoimmune diseases included herein arethose where a delayed hypersensitivity component has been establishedsuch as multiple sclerosis.

In the use of the present invention in transplant rejection phenomena,advantageous results ranging from prolongation of the viability of thetransplanted tissue to complete cessation of the rejection process areobtained. In the treatment of autoimmune diseases by the present method,advantageous results ranging from significant symptomatic relief tocessation of the underlying inflammatory process are obtained.

In treatment of the hyperimmunity diseases described above, therequisite clinical end-point is the suppression of the mammal's immuneresponse, thereby effecting amelioration of the hyperimmunity disease.Accordingly, the present invention contemplates use of effective dosagesof the compounds of substituted cyclized ω-carboxyalkyl carbanilic,carbamic acids and sulfurized analogs thereof described herein such thatthe disease progress is first halted and thereafter reversed. Amount ofthe compounds required depends upon a wide variety of factors includingthe particular compound selected, the age, weight and condition of themammal being treated, the severity of the particular hyperimmune diseasebeing treated, and the response of the mammal to treatment.

In order to obtain the efficacious results provided by the presentinvention, any systemic route of administration is acceptable. However,the preferred route of administration is by oral method although othersystemic routes of administration provide equivalent activity at theappropriate dose. Thus, oral, intravenous injection or infusion,subcutaneous injection, or administration in the form of rectal orvaginal suppository represent alternate routes of administration.Regardless of the route of administration selected, the cyclized acidsdescribed herein are formulated in a pharmaceutically acceptable form byconventional methods available in the pharmaceutical arts.

Accordingly, when compressed tablets are desired for oral administrationa compound of the present invention such as compounds heretoforedisclosed is combined with the desired inert ingredients and thereaftercompressed by conventional means into a tablet containing the desiredquantity of compound. In the case of parenteral administration, sterilesolutions for injection of infusion are prepared in accordance withreadily available techniques.

After the onset of the hyperimmunity disease has been diagnosed by theattending physician or veterinarian, the treatment with the substitutedcyclized mono or dithiocarbanilic acids or the cyclized mono ordithiocarbamic acids in accordance with the present method may beinitiated promptly. In cases where the cyclized compounds of the presentinvention are the sole immunosup- pressive agent to be employed in thetreatment of the hyperimmunity disease, an initial dosage between 1.0and 100 mg./kg./day, preferably 5.0 to 50.0 mg./kg./day, is employed.When initial dosages at the lower end of the above range are employed,the mammals progress is monitored and dosages on subsequent days areincreased in the event that the patient or animal response is deemed bythe attending physician or veterinarian to be absent or insufficient.When dosages as high as about 100 mg./kg./day are selected, the systemictoxicity of the cyclized compounds must be carefully evaluated andsubsequent dosages determined by evaluating the benefits of the drug inrelationship to any such toxic manifestations.

For convenience, dosages may be administered once daily or, morepreferably, administered at periodic intervals throughout the day.Accordingly, in man the cyclized mono- or dithiocarbanilic acid, andcyclized mono or dithiocarbamic acid derivatives are advantageouslyadministered at 4 or 8 hour intervals throughout the day.

The following examples and preparations describe the manner and processof making and using the invention and set forth the best modecontemplated by the inventor of carrying out the invention but are notto be construed as limiting.

All temperatures are in degrees centigrade.

DESCRIPTION OF THE PREFERRED EMBODIMENTS Intermediates

Preparation 1 ##STR14##

3-Mercaptopropionic acid (5.3 g., 50 mmol) is stirred in 200 ml.pyridine at room temperature. m-Acetyl phenylisothiocyanate (8.9 g.,50.2 mmol) is added and stirred for 30 minutes. Removal of the solventat 35°/1 mm gives an oil which slowly solidifies. Recrystallization fromchloroform-hexane gives a pale yellow solid (5.55 g., 39%) m.p.143°-145°.

Analysis: Calc'd for C₁₂ H₁₃ NO₃ S₂ : C. 50.9; H, 4.6; N, 4.9; S, 22.6.Found: C, 51.0; H, 4.6; H, 5.2; S, 22.8.

IR: max (Nujol) 326+ (NH), 1690 (C═O), 1665 (C═O) cm⁻¹.

Following the procedure of Preparation 1, but substituting theappropriate substituted phenyl isothiocyanate for m-acetylphenylisothiocyanate, the appropriate 3-[[[(substitutedphenyl)amino]thioxomethyl]thio]propionic acid is prepared as follows:

1. 3-[[[(2-acetylphenyl)amino]thioxomethyl]thio]propionic acid.

2. 3-[[[(4-acetylphenyl)amino]thioxomethyl]thio]propionic acid.

3. 3-[[[(2,3-diacetylphenyl)amino]thioxomethyl]thio]propionic acid.

4. 3-[[[(2,4-diacetylphenyl)amino]thioxomethyl]thio]propionic acid.

5. 3-[[[(2,5-diacetylphenyl)amino]thioxomethyl]thio]propionic acid.

6. 3-[[[(2,6-diacetylphenyl)amino]thioxomethyl]thio]propionic acid.

7. 3-[[[(3,4-diacetylphenyl)amino]thioxomethyl]thio]propionic acid.

8. 3-[[[(3,5-diacetylphenyl)amino]thioxomethyl]thio]propionic acid.

9. 3-[[[(2,4,6-triacetylphenyl)amino]thioxomethyl]thio]propionic acid.

10. 3-[[[(2,3,4-triacetylphenyl)amino]thioxomethyl]thio]propionic acid.

11. 3-[[[(3,4,5-triacetylphenyl)amino]thioxomethyl]thio]propionic acid.

12. 3-[[[(2,3,5-triacetylphenyl)amino]thioxomethyl]thio]propionic acid.

13. 3-[[[(2,4,5-triacetylphenyl)amino]thioxomethyl]thio]propionic acid.

14. 3-[[[(2,3,6-triacetylphenyl)amino]thioxomethyl]thio]propionic acid.

Preparation 2Bis-3,3'-[sulfonyl-bis(4,1-phenyleneaminocarbonothioylthio)]propionicacid. ##STR15##

To benzene (100 ml.) is added β-mercaptopropionic acid (3.20 g., B 30mmol), triethylamine (3.10 g., 30 mmol) andbis(4-isothiocyanatophenyl)sulfone (5.0 g., 15 mmol). The mixture isstirred for 30 minutes then 0.1 N NaOH (310 ml., 31 mmol) added.Acidification of the separated aqueous layer with 10% HCl precipitatedan off white solid which is recrystallized from methanol-water to leavebis-3,3'-[sulfonyl-bis(4,1-phenyleneaminocarbonothioylthio)]propionicacidas a pale yellow solid (6.08 g.): m.p. 173°-5°.

Analysis: Calc'd for C₂₀ H₂₀ N₂ O₆ S₅ : C, 44.1; H, 3.7; N, 5.1; S,29.4. Found: C, 44.0; H, 3.7; N, 5.1; S, 28.0.

IR: max (Nujol) 3200 (NH) 1700 (C═O) cm⁻¹.

Following the procedure of Preparation 2, but substituting anappropriate bis(isothiocyanatophenyl)sulfone the corresponding bis-3compound is prepared as follows:

1. bis-3,3'-[sulfonyl-bis(3,1-phenyleneaminocarbonothioylthio)]propionicacid.

2. bis-3,3'-[sulfonyl-bis(2,1-phenyleneaminocarbonothioylthio)]propionicacid.

Preparation 3 3-[[[(pentafluorophenyl)amino]thioxomethyl]thio]propanoicacid. ##STR16##

Pentafluorophenylisothiocyanate (2.25 g., 10 mmol) andβ-mercaptopropionic acid (1.1 g., 10 mmol) are stirred at roomtemperature in 25% aqueous trimethylamine (15 ml.). The flask is cooledinice and acidified with conc. HCl. A yellow gummy material separated,which is filtered, washed with water then dissolved in ether (100 ml.)and driedover MgSO₄. Removal of the solvent gives a pale yellow viscousoil (3.4 g.), which slowly crystallizes. Several attempts atrecystallizationsdo not give homogenous material. Chromatography overSiO₂ with 1:99 acetic acid:chloroform as eluent give pure material whichis recrystallized from ether-hexane as white plates of3-[[[(pentafluorophenyl)amino]thioxomethyl]thio]propanoic acid m.p.126.5°-129.0°.

Analysis: Calc'd for C₁₀ H₆ F₅ NO₂ S₂ : C, 36.3; H, 1.8; N, 4.2; S,19.3; F, 28.7. Found: C, 36.4; H, 1.8; N, 4.7; S, 19.2;F, 28.6.

IR: max (Nujol) 3175 (NH), 1704 (C═O) cm⁻¹.

Following the procedure of Preparation 3 but substituting theappropriate tri or tetra fluorophenylisothiocyanate the correspondingpropionic acid is formed as follows:

3-[[[(2,3,4-trifluorophenyl)amino]thioxomethyl]thio]propionic acid,

3-[[[(3,4,5-trifluorophenyl)amino]thioxomethyl]thio]propionic acid,

3-[[[(2,4,6-trifluorophenyl)amino]thioxomethyl]thio]propionic acid,

3-[[[(2,3,5-trifluorophenyl)amino]thioxomethyl]thio]propionic acid,

3-[[[(2,4,5-trifluorophenyl)amino]thioxomethyl]thio]propionic acid,

3-[[[(2,5,6-trifluorophenyl)amino]thioxomethyl]thio]propionic acid,

3-[[[(2,3,4,5-tetrafluorophenyl)amino]thioxomethyl]thio]propionic acid,

3-[[[(2,4,5,6-tetrafluorophenyl)amino]thioxomethyl]thio]propionic acid,

3-[[[(2,3,5,6-tetrafluorophenyl)amino]thioxomethyl]thio]propionic acid.

Example 1 3-(3-Acetylphenyl)tetrahydro-2-thioxo-4H-1,3-thiazin-4-one##STR17##

The propanoic acid (3.0 g., 10.6 mmol) is heated on a steam bath for 10minutes in acetic anhydride (15 ml.) containing 3 drops conc. H₂ SO₄.Upon cooling the solid is filtered (2.6g., 93%) and recrystallized fromchloroform-hexane to afford a yellow solid (1.6 g., 57%) m.p. 197°-199°.

Analysis: Calc'd for C₁₂ H₁₁ NO₂ S₂ : C, 54.3; H, 4.2; N, 5.3; S, 24.2.Found: C, 52.9; H, 4.4; N, 5.3; S, 23.8.

IR: max (Nujol) 1702 (C═O), 1674 (C═O) cm⁻¹.

Following the procedure of Example 1, but using the corresponding3-[[[(mono, di and tri substitutedacetylphenyl)amino]thioxomethyl]thio]propionic acid, there is obtained acorresponding product:

1. 3-(2-Acetylphenyl)tetrahydro-2-thioxo-4H-1,3-thiazin-4-one.

2. 3-(4-Acetylphenyl)tetrahydro-2-thioxo-4H-1,3-thiazin-4-one.

3. 3-(2,3-Diacetylphenyl)tetrahydro-2-thioxo-4H-1,3-thiazin-4-one.

4. 3-(2,4-Diacetylphenyl)tetrahydro-2-thioxo-4H-1,3-thiazin-4-one.

5. 3-(2,5-Diacetylphenyl)tetrahydro-2-thioxo-4H-1,3-thiazin-4-one.

6. 3-(2,6-Diacetylphenyl)tetrahydro-2-thioxo-4H-1,3-thiazin-4-one.

7. 3-(3,4-Diacetylphenyl)tetrahydro-2-thioxo-4H-1,3-thiazin-4-one.

8. 3-(3,5-Diacetylphenyl)tetrahydro-2-thioxo-4H-1,3-thiazin-4-one.

9. 3-(2,4,6-Triacetylphenyl)tetrahydro-2-thioxo-4H-1,3-thiazin-4-one.

10. 3-(2,3,4-Triacetylphenyl)tetrahydro-2-thioxo-4H-1,3-thiazin-4-one.

11. 3-(3,4,5-Triacetylphenyl)tetrahydro-2-thioxo-4H-1,3-thiazin-4-one.

12. 3-(2,3,5-Triacetylphenyl)tetrahydro-2-thioxo-4H-1,3-thiazin-4-one.

13. 3-(2,3,6-Triacetylphenyl)tetrahydro-2-thioxo-4H-1,3-thiazin-4-one.

14. 3-(2,4,5-Triacetylphenyl)tetrahydro-2-thioxo-4H-1,3-thiazin-4-one.

Example 2Bis-4,4-(3,3'-tetrahydro-2-thioxo-1,3-thiazinyl-4-one)-diphenylsulfone##STR18##

To the dithiocarbamate of Preparation 2 (3.0 g., 5.5 mmol), in aceticanhydride (15 ml.) is added 1 drop of conc. H₂ SO₄, and the reactionheated on a steam bath for 30 minutes. On cooling a solid crystallized(2.75 g.) which is recrystallized from dimethylformamide-water to yieldbis-4,4'-(3,3'-tetrahydro-2-thioxo-1,3-thiazinyl-4-one)diphenylsulfoneas yellow crystals (1.80 g.), m.p. 292°-294°.

Analysis: Calc'd for C₂₀ H₁₆ N₂ O₄ S₅ : C, 47.2; H, 3.2; N, 5.5; S,31.5. Found: C, 47.3; H, 3.5; N, 5.7; S, 30.9.

IR: max (Nujol) 1705 (C═O) cm⁻¹.

Following the procedure of Example 2, but using an appropriateintermediate,bis-3,3'[sulfonyl-bis-(phenyleneaminocarbonothioxo)]propionic acid,there is obtained a corresponding product as follows:

1.Bis-3,3'-(3,3'-tetrahydro-2-thioxo-1,3-thiazinyl-4-one)diphenylsulfone.

2.Bis-2,2'-(3,3'-tetrahydro-2-thioxo-1,3-thiazinyl-4-one)diphenylsulfone.

Example 3 3-(Pentafluorophenyl)tetrahydro-2-thioxo-4H-1,3-thiazin-4-one##STR19##

The carboxylic acid,3-[[[(pentafluorophenyl)amino]thioxomethyl]thio]propionic acid (500 mg.,1.51 mmol) is dissolved in acetic anhydride (5 ml.) to give a brightyellow solution. A drop of conc. H₂ SO₄ is added and the solution heatedon a steam bath for 2-3 minutes. On cooling, crystals separated, whichare recrystallized from ethanol to give pure3-(pentafluorophenyl)tetrahydro-2-thioxo-4H-1,3-thiazin-4-one as brightyellow translucent crystals (320 mg.) m.p. 163.5°-164.5°.

Analysis: Calc'd. for C₁₀ H₄ F₅ NOS₂ : C, 38.3; H, 1.3;N, 4.5; S, 20.4;F, 30.3. Found: C, 38.5; H, 1.1; N, 4.6; S, 20.4; F, 29.9.

IR: max (Nujol) 1730 (C═O) cm⁻¹.

Following the procedure of Example 3 but using an appropriate tri ortetra fluorophenyl amino[[thioxomethyl]thio]propionic acid there isobtained a corresponding product as follows:

1. 3-(3,4,5-trifluorophenyl)tetrahydro-2-thioxo-4H-1,3-thiazin-4-one.

2. 3-(2,3,4-trifluorophenyl)tetrahydro-2-thioxo-4H-1,3-thiazin-4-one.

3. 3-(2,4,6-trifluorophenyl)tetrahydro-2-thioxo-4H-1,3-thiazin-4-one.

4. 3-(2,3,5-trifluorophenyl)tetrahydro-2-thioxo-4H-1,3-thiazin-4-one.

5. 3-(2,4,5-trifluorophenyl)tetrahydro-2-thioxo-4H-1,3-thiazin-4-one.

6. 3-(2,5,6-trifluorophenyl)tetrahydro-2-thioxo-4H-1,3-thiazin-4-one.

7.3-(2,3,4,5-tetrafluorophenyl)tetrahydro-2-thioxo-4H-1,3-thiazin-4-one.

8.3-(2,4,5,6-tetrafluorophenyl)tetrahydro-2-thioxo-4H-1,3-thiazin-4-one.

9.3-(2,3,5,6-tetrafluorophenyl)tetrahydro-2-thioxo-4H-1,3-thiazin-4-one.

Example 43-(3-Fluorophenyl)tetrahydro-2-thioxo-5-acetylamino-4H-1,3-thiazin-4-one##STR20##

N-Acetylcysteine (2.36 g., 20 mmol) is mixed with benzene (50 ml.) andtriethylamine (2.02 g., 20 mmol) followed by3-fluorophenylisothiocyanate (3.06 g., 20 mmol). The reaction is stirredfor 15 minutes when 0.1 N-NaOH solution (200 ml., 20 mmol) is addedfollowed by ether (50 ml.). The aqueous layer is separated and acidifiedwith 10% HCl. A yellow oil separated which is extracted withethylacetate (200 ml.) and dried over MgSO₄. Filtration and removal ofthe solvent gives a yellow foam (4.7g.). Chromatography over SiO₂eluting with acetic acid-chloroform mixtures produces a yellow gum (4.3g.) of the intermediate dithiocarbamate. The gum is partitioned betweenether (250 ml.) and water (150 ml.); the ether is washed with 2×150 ml.water. After drying (MgSO₄), the ether layer affords a yellow foam (3.0g.). The aqueous layers afford a similar yellow foam (870 mg.) uponevaporation, identical in all respects to the former yellow foam. Thelatter material (870 mg.) is treated with acetic anhydride (5 ml.) and 3crops conc. H₂ SO₄ to give a brilliant yellow solution. The solution isheated for 5minutes on a steam bath, cooled and water (150 ml.) added togive a yellow gum. Extraction with 2×150 ml. ethylacetate gives a yellowglass (800 mg.). Chromatography over SiO₂, eluting with 1:9methanol:chloroform gives a yellow solid (650 mg.). Severalrecrystallizations gives small yellow granules of3-(3-fluorophenyl)tetrahydro-2-thioxo-5-acetylamino-4H-1,3-thiazin-4-one,m.p. 176°-7°.

Analysis: Calc'd for C₁₂ H₁₁ FN₂ O₂ S₂ : C, 48.3; H, 3.7; N, 9.4. Found:C, 48.5; H, 3.7; N, 9.5.

IR: max (Nujol) 3330 (NH), 1720 (C═O), 1670 (C═O) cm⁻¹.

Following the procedures of Example 4 but using an appropriateintermediateselected from a [[[(mono, di, tri, tetra and penta fluorosubstituted phenyl)]thioxomethyl]thio]propionic acid there is acorresponding product:

1.3-(2-fluorophenyl)tetrahydro-2-thioxo-5-acetylamino-4H-1,3-thiazin-4-one.

2.3-(4-fluorophenyl)tetrahydro-2-thioxo-5-acetylamio-4H-1,3-thiazin-4-one.

3.3-(2,3-difluorophenyl)tetrahydro-2-thioxo-5-acetylamino-4H-1,3-thiazin-4-one.

4.3-(2,4-difluorophenyl)tetrahydro-2-thioxo-5-acetylamino-4H-1,3-thiazin-4-one.

5.3-(2,5-difluorophenyl)tetrahydro-2-thioxo-5-acetylamino-4H-1,3-thiazin-4-one.

6.3-(2,6-difluorophenyl)tetrahydro-2-thioxo-5-acetylamino-4H-1,3-thiazin-4-one.

7.3-(3,4-difluorophenyl)tetrahydro-2-thioxo-5-acetylamio-4H-1,3-thiazin-4-one.

8.3-(3,5-difluorophenyl)tetrahydro-2-thioxo-5-acetylamino-4H-1,3-thiazin-4-one.

9.3-(2,4,6-trifluorophenyl)tetrahydro-2-thioxo-5-acetylamino-4H-1,3-thiazin-4-one.

10.3-(2,3,4-trifluorophenyl)tetrahydro-2-thioxo-5-acetylamino-4H-1,3-thiazin-4-one.

11.3-(3,4,5-trifluorophenyl)tetrahydro-2-thioxo-5-acetylamino-4H-1,3-thiazin-4-one.

12.3-(2,3,5-trifluorophenyl)tetrahydro-2-thioxo-5-acetylamino-4H-1,3-thiazin-4-one.

13.3-(2,4,5-trifluorophenyl)tetrahydro-2-thioxo-5-acetylamino-4H-1,3-thiazin-4-one.

14.3-(2,3,6-trifluorophenyl)tetrahydro-2-thioxo-5-acetylamino-4H-1,3-thiazin-4-one.

15.3-(2,3,4,5-tetrafluorophenyl)tetrahydro-2-thioxo-5-acetylamino-4H-1,3-thiazin-4-one.

16.3-(2,3,5,6-tetrafluorophenyl)tetrahydro-2-thioxo-5-acetylamino-4H-1,3-thiazin-4-one.

17.3-(2,3,4,6-tetrafluorophenyl)tetrahydro-2-thioxo-5-acetylamino-4H-1,3-thiazin-4-one.

18.3-(2,3,4,5,6-pentafluorophenyl)tetrahydro-2-thioxo-5-acetylamino-4H-1,3-thiazin-4-one.

Following the procedures of Preparations 1, 2, and 3 the intermediatesof the following Tables I, II, and III, respectively are prepared fromcorresponding reactants:

                                      TABLE I                                     __________________________________________________________________________     ##STR21##                                                                    R.sub.1         R.sub.2          R.sub.3           R.sub.4                                                                             R.sub.5              __________________________________________________________________________    COCH.sub.3      H                H                 H     H                    H               COCH.sub.3       H                 H     H                    H               H                COCH.sub.3        H     H                    H               COCH.sub.3       H                 H     COCH.sub.3           COCH.sub.3      H                H                 H     COCH.sub.3           COCH.sub.3      COCH.sub.3       H                 H     H                    COCH.sub.3      H                COCH.sub.3        H     H                    H               COCH.sub.3       H                 COCH.sub.3                                                                          H                    H               H                COCH.sub.3        COCH.sub.3                                                                          H                    COCH.sub.3      COCH.sub.3       COCH.sub.3        H     H                    COCH.sub.3      H                COCH.sub.3        H     COCH.sub.3           H               COCH.sub.3       COCH.sub.3        COCH.sub.3                                                                          H                    COCH.sub.3      COCH.sub.3       H                 COCH.sub.3                                                                          H                    COCH.sub.3      H                H                 COCH.sub.3                                                                          COCH.sub.3           H               COCH.sub.3       COCH.sub.3              COCH.sub.3           H               H                                                                                               ##STR22##        H     H                                     ##STR23##       H                 H     H                     ##STR24##      H                H                 H     H                    F               F                F                 F     F                    F               H                F                 H     F                    F               F                F                 H     H                    H               F                F                 F     H                    F               F                H                 F     H                    F               H                F                 F     H                    F               H                H                 F     F                    F               F                F                 F     H                    F               H                F                 F     F                    F               F                H                 F     F                    __________________________________________________________________________

Following the procedures of Example 1, 2, and 3, novel compounds of thefollowing Table II are prepared from the corresponding intermediates ofTable I.

                                      TABLE II                                    __________________________________________________________________________     ##STR25##                                                                    R1          R2            R3             R4    R5                             __________________________________________________________________________    COCH.sub.3  H             H              H     H                              H           COCH.sub.3    H              H     H                              H           H             COCH.sub.3     H     H                              COCH.sub.3  H             H              COCH.sub.3                                                                          H                              COCH.sub.3  H             H              H     COCH.sub.3                     COCH.sub.3  COCH.sub.3    H              H     H                              COCH.sub.3  H             COCH.sub.3     H     H                              H           COCH.sub.3    H              COCH.sub.3                                                                          H                              H           COCH.sub.3    COCH.sub.3     H     H                              COCH.sub.3  COCH.sub.3    COCH.sub.3     H     H                              COCH.sub.3  H             COCH.sub.3     H     COCH.sub.3                     H           COCH.sub.3    COCH.sub.3     COCH.sub.3                                                                          H                              COCH.sub.3  COCH.sub.3    H              COCH.sub.3                                                                          H                              COCH.sub.3  H             H              COCH.sub.3                                                                          COCH.sub.3                     COCH.sub.3  H             COCH.sub.3     COCH.sub.3                                                                          H                              H           H                                                                                            ##STR26##     H     H                                           ##STR27##    H              H     H                               ##STR28##                H              H     H                              F           F             F              F     F                              F           H             F              H     F                              F           F             F              H     H                              H           F             F              F     H                              F           F             H              F     H                              F           H             F              F     H                              F           H             H              F     F                              F           F             F              F     H                              F           H             F              F     F                              F           F             H              F     F                              __________________________________________________________________________

Following the procedures of Example 4, novel compounds of the followingTable III are prepared from corresponding reactants, themselves known inthe art.

    ______________________________________                                         ##STR29##                                                                    R.sub.1                                                                             R.sub.2   R.sub.3                                                                             R.sub.4 R.sub.5                                                                           R.sub.6                                     ______________________________________                                        F     F         F     F       F                                                                                  ##STR30##                                  F     H         H     H       H                                                                                  ##STR31##                                  H     F         H     H       H                                                                                  ##STR32##                                  H     H         F     H       H                                                                                  ##STR33##                                  F     F         H     H       H                                                                                  ##STR34##                                  F     H         F     H       H                                                                                  ##STR35##                                  F     H         H     F       H                                                                                  ##STR36##                                  F     H         H     H       F                                                                                  ##STR37##                                  H     F         F     H       H                                                                                  ##STR38##                                  H     F         H     F       H                                                                                  ##STR39##                                  H     F         F     H       F                                                                                  ##STR40##                                  F     H         F     H       F                                                                                  ##STR41##                                  F     F         F     H       H                                                                                  ##STR42##                                  H     F         F     F       H                                                                                  ##STR43##                                  F     F         H     F       H                                                                                  ##STR44##                                  F     F         H     H       F                                                                                  ##STR45##                                  F     F         F     F       H                                                                                  ##STR46##                                  F     F         H     F       F                                                                                  ##STR47##                                  F     F         F     H       F                                                                                  ##STR48##                                  ______________________________________                                    

We claim:
 1. A method of treating a mammal exhibiting allographicrejection phenomena from tissue transplantation whichcomprises:systemically administering to said mammal in apharmaceutically acceptable dosage form a compound selected from thegroup consisting of: ##STR49## wherein T is selected from the groupconsisting of hydrogen; lower alkyl, of from one to four carbon atoms,amino; carboxybenzylideneamino; chlorobenzylideneamine; anilino;α-alkylbenzyl with alkyl of from one to four carbon atoms, inclusive;cycloalkyl, and ##STR50## wherein R is selected from the groupconsisting of hydrogen; alkyl, of from one to four carbon atoms,inclusive; alkoxy, of from one to four carbon atoms; thioalkoxy, of fromone to four carbon atoms, inclusive; alkylcarbonyl, with alkyl of fromone to four carbon atoms, inclusive; acyloxy with acyl of from one tofour carbon atoms, inclusive; nitro; acylamino of from one to fourcarbon atoms, inclusive; and ##STR51## wherein a is the integer one andR₃ and R₄ are different and are selected from the group consisting ofhydrogen, methyl, carboxymethyl, ethoxymethylene, and indanylmethylenesuch that at least one selection is hydrogen, wherein n₁ is an integerof from one to three; wherein Y is sulfur; in not less than a non-toxicamount effective to prolong the viability of the transplanted tissue. 2.A method of treating a mammal exhibiting allographic rejection phenomenafrom tissue transplantation which comprises:systemically administeringto said mammal in a pharmaceutically acceptable dosage form a compoundselected from the group consisting of: ##STR52## wherein T is selectedfrom the group consisting of hydrogen; lower alkyl of from one to fourcarbon atoms; amino, carbobenzylideneamino; chlorobenzylideneamino;anilino; α-alkylbenzyl with alkyl of from one to four carbon atoms,inclusive, cycloalkyl, and ##STR53## wherein R is selected from thegroup consisting of hydrogen; alkyl of from one to four carbon atoms,inclusive, alkoxy of from one to four carbon atoms; thioalkoxy of fromone to four carbon atoms, inclusive; alkylcarbonyl, with alkyl of fromone to four carbon atoms, inclusive: acyloxy with acyl of from one tofour carbon atoms, inclusive; nitro; acylamino of from one to fourcarbon atoms, inclusive; and ##STR54## wherein R₃ and R₄ are hydrogen;wherein n₁ is an integer of one to three; wherein a is the integer one;wherein Y is sulfur; in not less than a non-toxic amount effective toprolong the viability of the transplanted tissue.
 3. A method oftreating a mammal exhibiting allographic rejection phenomenon fromtissue transplantation which comprises:systemically administering tosaid mammal in a pharmaceutically acceptable dosage form a compound ofthe formula: ##STR55## wherein R₆ is selected from the group consistingof acylamino with acyl of from one to four carbon atoms, inclusive;wherein n₂ is an integer of from one to five; wherein R" is selectedfrom the group consisting of chloro, bromo, fluoro, and trifluoromethyl;wherein Y is oxygen or sulfur; in not less than a non-toxic amounteffective to prolong the viability of the transplanted tissue.
 4. Amethod of treating a mammal exhibiting allographic rejection phenomenafrom tissue transplantation which comprises systemically administeringto said mammal in a pharmaceutically acceptable dosage form a compoundselected from the group consistingof:3-methyltetrahydro-2-thioxo-4H-1,3-thiazin-4-one;3-cyclohexyltetrahydro-2-thioxo-4H-1,3-thiazin-4-one;and3-α-methylbenzyltetrahydro-2-thioxo-4H-1,3-thiazin-4-one in not lessthan a non-toxic amount effective to prolong the viability of thetransplanted tissue.
 5. A method of treating a mammal exhibitingallographic rejection phenomena from tissue implantation whichcomprises:systemically administering to said mammal in apharmaceutically acceptable dosage form a compound having the formula:##STR56## wherein R₇ and R₈ are the same or different and are selectedfrom the group consisting of hydrogen, alkyl of from one to four carbonatoms, inclusive, and carboxyalkyl with alkyl of from one to four carbonatoms, inclusive, and pharmaceutically acceptable salts thereof; suchthat when R₇ and R₈ are different one of the selections ishydrogen;wherein R" is selected from the group consisting of bromo,chloro, fluoro, and trifluoromethyl; wherein Y is selected from thegroup consisting of sulfur and oxygen; wherein n₂ is an integer of fromone to five;in not less than a non-toxic amount effective to prolongviability of the transplanted tissue.
 6. A method of treating a mammalexhibiting allographic rejection phenomena from tissue transplantationwhich comprises:systemically administering to said mammal in apharmaceutically acceptable dosage form a compound selected from thegroup consisting of:5-(ethoxymethylene)rhodanine;5-(5-indanylmethylene)rhodanine; 3-phenyl-5-methylrhodanine; and3-phenyl-5-carboxymethylrhodaninein not less than a non-toxic amounteffective to prolong the viability of the transplanted tissue.
 7. Amethod of treating a mammal exhibiting rheumatoid arthritis, psoriaticarthritis, systemic lupus erythematosus, regional enteritis, chronicactive hepatitis, nephrotic syndrome, glomerulonephritis, lupusnephritis, ulcerative colitis, and multiple sclerosis whichcomprises:systemically administering to said mammal in apharmaceutically acceptable dosage form a compound selected from thegroup consisting of: ##STR57## wherein T is selected from the groupconsisting of hydrogen; lower alkyl of from one to four carbon atoms;amino, carbobenzylideneamino; chlorobenzylideneamino; anilino;α-alkylbenzyl with alkyl of from one to four carbon atoms, inclusive,cycloalkyl, and ##STR58## wherein R is selected from the groupconsisting of hydrogen; alkyl of from one to four carbon atoms,inclusive, alkoxy of from one to four carbon atoms; thioalkoxy of fromone to four carbon atoms, inclusive; alkylcarbonyl, with alkyl of fromone to four carbon atoms, inclusive; acyloxy with acyl of from one tofour carbon atoms, inclusive; nitro; acylamino of from one to fourcarbon atoms, inclusive; and ##STR59## wherein a is the integer one andR₃ and R₄ are different and are selected from the group consisting ofhydrogen, methyl, carboxymethyl, ethoxymethylene, and indanylmethylenesuch that at least one selection is hydrogen, wherein n₁ is an integerof one to three; wherein Y is sulfur;in not less than a non-toxic amounteffective to induce significant relief.
 8. A method according to claims2 or 7 wherein said compound is selected from the group consistingof:3-phenylrhodanine; 3-(3-methoxyphenyl)rhodanine;3-(3-methylphenyl)rhodanine; 3-(3-nitrophenyl)rhodanine;3-(4-acetylaminophenyl)rhodanine.
 9. A method according to claims 2 or 7wherein said compound is selected from the group consistingof:3-phenylmethylene rhodanine; 3-aminorhodanine;3-(2-carboxybenzylideneamino)rhodanine;3-(4-chlorobenzylideneamino)rhodanine; and 3-anilinorhodanine.
 10. Amethod of treating a mammal exhibiting rhematoid arthritis, psoriaticarthritis, systemic lupus erythematosus, regional enteritis, chronicactive hepatitis, nephrotic syndrome, glomerulonephritis, lupusnephritis, ulcerative colitis, and multiple sclerosis whichcomprises:systemically administering to said mammal in apharmaceutically acceptable dosage form a compound of the formula:##STR60## wherein R₆ is selected from the group consisting of acylaminowith acyl of from one to four carbon atoms, inclusive, wherein n₂ is aninteger of from one to five; wherein R" is selected from the groupconsisting of chloro, bromo, fluoro, and trifluoromethyl; wherein Y isoxygen or sulfur;in not less than a non-toxic amount effective to inducesignificant symptomatic relief.
 11. A method according to claim 3 or 10wherein said compound is3-(3-fluorophenyl)-5-acetylamino-tetrahydro-2-thioxo-4H-1,3-thiazin-4-one.12. A method of treating a mammal exhibiting rheumatoid arthritis,psoriatic arthritis, systemic lupus erythematosus, regional enteritis,chronic active hepatitis, nephrotic syndrome, glomerulonephritis, lupusnephritis, ulcerative colitis, and multiple sclerosis whichcomprises:systemically administering to said mammal in apharmaceutically acceptable dosage form a compound having the formula:##STR61## wherein R₇ and R₈ are the same or different and are selectedfrom the group consisting of hydrogen, alkyl of from one to four carbonatoms, inclusive, and carboxyalkyl whith alkyl of from one to fourcarbon atoms, inclusive, and pharmaceutically acceptable salts thereof;wherein R" is selected from the group consisting of bromo, chloro,fluoro, and trifluoromethyl; wherein Y is selected from the groupconsisting of sulfur and oxygen; wherein n₂ is an integer of from one tofive; in not less than a non-toxic amount effective to inducesignificant symptomatic relief.
 13. A method according to claim 5 or 12wherein said compound is 3-(3-fluorophenyl)rhodanine.
 14. A method oftreating a mammal exhibiting rheumatoid arthritis, psoriatic arthritis,systemic lupus erythematosus, regional enteritis, chronic activehepatitis, nephrotic syndrome, glomerulonephritis, lupus nephritis,ulcerative colitis and multiple sclerois which comprises:systemicallyadministering to said mammal in a pharmaceutically acceptable dosageform a compound selected from the group consisting of: ##STR62## whereinT is selected from the group consisting of hydrogen; lower alkyl, offrom one to four carbon atoms, amino; carboxylbenzylideneamino;chlorobenzylideneamino; anilino; α-alkylbenzyl with alkyl of from one tofour carbon atoms; inclusive; cycloalkyl; and ##STR63## wherein R isselected from the group consisting of hydrogen; alkyl of from one tofour carbon atoms, inclusive; alkoxy, of from one to four carbon atoms,thioalkoxy, of from one to four carbon atoms, inclusive; alkylcarbonyl,with alkyl of from one to four carbon atoms, inclusive; acyloxy withacyl of from one to four carbon atoms, inclusive; nitro; acylamino offrom one to four carbon atoms, inclusive; and ##STR64## wherein a is theinteger one and R₃ and R₄ are different and are selected from the groupconsisting of hydrogen, methyl, carboxymethyl, ethoxymethylene, andindanylmethylene such that at least one selection is hydrogen, whereinn₁ is an integer of from one to three; wherein Y is sulfur;in not lessthan a non-toxic amount effective to induce significant relief.
 15. Amethod of treating a mammal exhibiting rheumatoid arthritis, psoriaticarthritis, systemic lupus erythematosus, regional enteritis, chronicactive hepatitis, nephrotic syndrome, glomerulonephritis, lupusnephritis, ulcerative colitis and multiple sclerosis whichcomprises:systemically administering to said mammal in apharmaceutically acceptable dosage form a compound selected from thegroup consisting of:3-methyltetrahydro-2-thioxo-4H-1,3-thiazin-4-one;3-cyclohexyltetrahydro-2-thioxo-4H-1,3-thiazin-4-one;3-α-methylbenzyltetrahydro-2-thioxo-4H-1,3-thiazin-4-onein not less thana non-toxic amount effective to induce significant relief.
 16. A methodof treating a mammal exhibiting rheumatoid arthritis, psoriaticarthritis, systemic lupus erythematosus, regional enteritis, chronicactive hepatitis, nephrotic syndrome, glomerulonephritis, lupusnephritis, ulcerative colitis and multiple sclerosis whichcomprises:systemically administering to said mammal in apharmaceutically acceptable dosage form a compound selected from thegroup consisting of:5-(ethoxymethylene)rhodanine;5-(5-indanylmethylene)rhodanine; 3-phenyl-5-methylrhodanine; and3-phenyl-5-carboxymethylrhodaninein not less than a non-toxic amounteffective to induce significant relief.